The hypothesis that increased opiodergic neurotransmission contributes to the pathophysiology of cholestasis, and in particular to the pruritus associated with this syndrome was tested. In a double-blind placebo controlled trial of 29 patients with pruritus from cholestatic liver diseases, naloxone infusions were associated with decreased scratching activity and decreased perception of pruritus (as assessed by a visual analogue scale). The use of the oral opioid antagonist nalmefene had also been evaluated in 17 patients with this form of pruritus, and was found to be associated with decreased scratching activity and visual analogue score (VAS). Based on these findings, a double-blind placebo controlled trial of nalmefene was conducted in 11 patients with the pruritis of cholestasis. Nalmefene was associated with a 75% reduction of scratching activity and an 86% reduction in the VAS, cholestasis and suggest that nalmefene may be useful on the treatment of this form of pruritus. Adult cholestatic livers from rats with cholestasis secondary to bile duct resection express preproenkephalin (ppENK) mRNA in the proliferating bile ductules and appear to make endogenous opioids de novo. to further study the status of the opioid system in cholestasis the content of proenkephalin-derived endogenous opioids was measured in bile duct resected livers and in controls. Cholestatic livers had significantly higher concentration of endogenous opioids suggesting that they accumulate in the liver in cholestasis and most likely, synthesize them de novo. ppENK mRNA was sought in the livers of patients with PBC in baseline liver biopsies and during methotrexate treatment by the use of a solution hybridization assay. No ppENK mRNA was found.